Although improved reperfusion strategies have led to declined mortality in non-diabetic patients after acute myocardial infarction, both prevalence and severity of post-MI heart failure (HF) continually escalates in patients with type 2 diabetes, a disease affecting >20 million people in the US. Increasing evidence demonstrates cardiometabolic dysregulation contributes significantly to HF progression. Approaches targeting more efficient substrate use and preservation of cardiac metabolism are increasingly recognized as effective therapeutic strategies against HF. Adiponectin (APN) is a novel adipokine with fundamental metabolic regulatory, anti-inflammatory, and anti-diabetic roles. Its cardioprotective roles are well-recognized both clinically and experimentally. Increasing evidence suggests biological response to APN is significantly impaired in HF patients, contributing to systemic and cardiac metabolic dysregulation and HF progression. However, mechanisms leading to impaired APN cardiovascular regulation remain unclear. Our preliminary experiments strongly support GRK2-mediated AdipoR1 phosphorylation with resultant APN signaling impairment is a significant risk factor contributing to cardiometabolic dysfunction and HF progression, particularly during diabetic conditions. This hypothesis will be rigorously investigated by identifying the specific phosphorylation sites responsible for inhibition of AdipoR1 by GRK2 (Aim 1), defining the molecular mechanisms responsible for impaired APN signaling when AdipoR1 is phosphorylated (Aim 2), and clarifying whether the molecular interventions capable of blocking AdipoR1 phosphorylation may restore cardioprotective signaling and attenuate HF progression, particularly in the diabetic heart (Aim 3). Successful completion of the proposed experiments will not only define novel molecular mechanisms leading to cardiometabolic disturbances in the failing heart, but may also identify novel targets improving cardiometabolism, attenuating HF, and reducing HF mortality, particular in diabetics. The novel data resulting from this application's proposed studies will therefore be both scientifically significant and clinically important.